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United States Patent |
5,620,970
|
Han
,   et al.
|
April 15, 1997
|
Topical ophthalmic carbonic anhydrase inhibitor formulations
Abstract
The present invention is directed to topical ophthalmic formulations of
carbonic anhydrase inhibitors and polyethoxylated derivatives of castor
oil. Methods for using the formulations for treating and controlling
glaucoma and ocular hypertension are also disclosed.
Inventors:
|
Han; Wesley W. (Fort Worth, TX);
Dean; Thomas R. (Weatherford, TX);
Gerson; Steven H. (Fort Worth, TX);
Ali; Yusuf (Fort Worth, TX);
Jani; Rajni (Fort Worth, TX)
|
Assignee:
|
Alcon Laboratories, Inc. (Fort Worth, TX)
|
Appl. No.:
|
461329 |
Filed:
|
June 5, 1995 |
Current U.S. Class: |
514/222.8; 424/731; 514/224.2; 514/226.5; 514/232.5; 514/233.8; 514/316; 514/318; 514/321; 514/338; 514/373; 514/422; 514/432; 514/762; 514/912; 514/913; 514/914 |
Intern'l Class: |
A61J 001/05; A61K 009/08; A61K 031/355; A61K 047/34; 912; 913; 914 |
Field of Search: |
514/211,212,222.8,224.2,226.5,232.5,233.8,253,316,318,321,338,373,432,422,762
|
References Cited
U.S. Patent Documents
4797413 | Jan., 1989 | Baldwin et al. | 514/432.
|
4829088 | May., 1989 | Doulakas | 514/567.
|
4960799 | Oct., 1990 | Nagy | 514/567.
|
5147647 | Sep., 1992 | Darougar | 424/427.
|
5153192 | Oct., 1992 | Dean et al. | 514/226.
|
5240923 | Aug., 1993 | Dean et al. | 514/226.
|
5378703 | Jan., 1995 | Dean et al. | 514/222.
|
Other References
Hata, Murano, and Ueda, CA 118:261059, Ophthalmic Solutions Containing
Cyclosporin and Surfactants (1993).
Koide, CA 122:17250, Vitamin A-Solubilized Eye Drops (1995).
Fukahori, Uchino, and Takahashi, CA 118:109767, Aqueous Vitamin E Solutions
Containing Surfactants (1993).
Fukahori, Takahashi, and Uchino, CA 114:254038, Stable Eye Drops Containing
Vitamin E, FAD Sodium Salt, Allantoin, and Glycyrrhizin (1991).
Takahashi, Fukahori, Uchino, and Eino, CA 114:254039, Stable FAD Sodium
Salt or Cyanocobalamine Eye Drops (1991).
Koide and Kojima, CA 120:86468, Stable Eyedrops of Naphazoline Containing
Nonionic Surfactants and Glycyrrhizinate Salts (1994).
Koide, CA121:91816, Stable Solutions Containing Solubilized Vitamin A
Derivatives (1994).
Koide and Aoshima, CA 121:308384, Stable Vitamin A-and E-Solubilized Eye
Drops (1994).
|
Primary Examiner: Nutter; Nathan M.
Attorney, Agent or Firm: Yeager; Sally
Claims
What is claimed is:
1. A topical ophthalmic composition for treating and controlling glaucoma
and ocular hypertension comprising 0.1-10.0 wt. % of a carbonic anhydrase
inhibitor and 0.01-10.0 wt. % of a polyethoxylated derivative of castor
oil resulting from the reaction of from 2-200 moles of ethylene oxide per
1 mole of castor oil, wherein said derivatives can be hydrogenated.
2. The composition of claim 1 wherein the polyethoxylated derivative of
castor oil results from the reaction of 35 moles of ethylene oxide with 1
mole of castor oil.
3. The composition of claim 1 wherein the carbonic anhydrase inhibitor is
selected from the group consisting of
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide (1-methyl)ethyl ester
hydrochloride; (R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,
4-dihydro-2H-thieno[3,2-e]-1, 2-thiazine-2-butanoic acid 1, 1-dioxide
ethyl ester hydrochloride; (S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride; and
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide.
4. The composition of claim 1 which further comprises a preservative at a
concentration of 0.001-0.1 wt. %.
5. The composition of claim 4 wherein the preservative is benzalkonium
chloride.
6. A topical ophthalmic composition for treating and controlling glaucoma
and ocular hypertension comprising 0.1-10.0 wt. % of a carbonic anhydrase
inhibitor selected from the group consisting of
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide (1-methyl)ethyl ester
hydrochloride; (R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,
4-dihydro-2H-thieno[3,2-e]-1, 2-thiazine-2-butanoic acid 1, 1-dioxide
ethyl ester hydrochloride; (S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride; and
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide; 0.01-10.0 wt. % of a
polyethoxylated derivative of castor oil resulting from the reaction of 35
moles of ethylene oxide with 1 mole of castor oil; and 0.001-0.1 wt. %
benzalkonium chloride.
7. A method for treating and controlling glaucoma which comprises
administering a pharmaceutically effective amount of a composition of
0.1-10.0 wt. % of a carbonic anhydrase inhibitor and 0.01-10.0 wt. % of a
polyethoxylated derivative of castor oil resulting from the reaction of
from 2-200 moles of ethylene oxide per 1 mole of castor oil, wherein said
derivatives can be hydrogenated to an affected eye.
8. The method of claim 7 wherein the polyethoxylated derivative of castor
oil results from the reaction of 35 moles of ethylene oxide with 1 mole of
castor oil.
9. The method of claim 7 wherein the carbonic anhydrase inhibitor is
selected from the group consisting of
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide (1-methyl)ethyl ester
hydrochloride; (R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,
4-dihydro-2H-thieno[3,2-e]-1, 2-thiazine-2-butanoic acid 1, 1-dioxide
ethyl ester hydrochloride; (S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride; and
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide.
10. The method of claim 7 wherein the composition further comprises a
preservative at a concentration of 0.001-0.1 wt. %.
11. The method of claim 10 wherein the preservative is benzalkonium
chloride.
12. A method for treating and controlling glaucoma and ocular hypertension
which comprises administering a pharmaceutically effective amount of a
composition comprising 0.1-10.0 wt. % of a carbonic anhydrase inhibitor
selected from the group consisting of
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide (1-methyl)ethyl ester
hydrochloride; (R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,
4-dihydro-2H-thieno[3,2-e]-1, 2-thiazine-2-butanoic acid 1, 1-dioxide
ethyl ester hydrochloride; (S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride; and
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide; 0.01-10.0 wt. % of a
polyethoxylated derivative of castor oil resulting from the reaction of 35
moles of ethylene oxide with 1 mole of castor oil; and 0.001-0.1 wt. %
benzalkonium chloride.
Description
The present invention is directed to topical ophthalmic formulations useful
for treating and controlling glaucoma and ocular hypertension.
BACKGROUND OF THE INVENTION
The use of certain polyethoxylated ether derivatives of castor oil as
surfactants and/or emulsifiers in topical ophthalmic formulations is
known. See Hata, Murano, and Ueda, CA 118:261059, Ophthalmic solutions
containing cyclosporin and surfactants; Koide, CA 122:17250, Vitamin
A-solubilized eye drops; Fukahori, Uchino, and Takahashi, CA 118:109767,
Aqueous vitamin E solutions containing surfactants; Fukahori, Takahashi,
and Uchino, CA 114:254038, Stable eye drops containing vitamin E, FAD
sodium salt, allantoin, and glycyrrhizin; Takahashi, Fukahori, Uchino, and
Eino, CA 114:254039, Stable FAD sodium salt or cyanocobalamine eye drops;
Koide and Kojima, CA 120:86468, Stable eyedrops of naphazoline containing
nonionic surfactants and glycyrrhizinate salts; Koide, CA 121:91816,
Stable solutions containing solubilized vitamin A derivatives; Nagy, U.S.
Pat. No. 4,960,799, Stabilized Aqueous Solutions of Pharmaceutically
Acceptable Salts of Ortho-(2,6-Dichtorophenyl)-Amino-Phenylacetic Acid for
Ophthalmic Use, Oct. 2, 1990 and related Product Insert for Voltaren
Ophthalmic; Doulakas, U.S. Pat. No. 4,829,088, Medicament for the
Treatment of Inflammations of the Eye, May 9, 1989; and Koide and Aoshima,
CA 121:308384, Stable Vitamin A- and E-solubilized eye drops.
The use of carbonic anhydrase inhibitors (CAIs) in topical ophthalmic
formulations for lowering intraocular pressure is known. See, for example,
U.S. Pat. Nos. 5,153,192; 5,240,923; 5,378,703; and 4,797,413. Although
CAIs are very useful in lowering intraocular pressure, they are typically
difficult to formulate at physiological pH due to their sparing solubility
except at uncomfortably low pHs. Formulation has also proved challenging
due to the instability of some CAIs.
The compositions of the present invention overcome the problems associated
with prior CAI compositions in that they are comfortable and stable.
SUMMARY OF THE INVENTION
The compositions of the present invention contain a CAI, and a
polyethoxylated ether derivative of castor oil. The invention also
includes methods for treating and controlling glaucoma and ocular
hypertension by administering the compositions topically to an affected
mammalian eye.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The compositions of this invention contain a CAI and a polyethoxylated
derivative of castor oil. The compositions are efficacious in treating and
controlling glaucoma and ocular hypertension. In addition, the
compositions are surprisingly comfortable and stable and the efficacy of
the composition's preservative is maintained.
The compositions contain a CAI, such as those disclosed in U.S. Pat. Nos.
5,153,192; 5,240,923; 5,378,703; and 4,797,413, the contents of which are
incorporated by reference.
The compositions also contain a polyethoxylated derivative of castor oil.
These derivatives are formed by the ethoxylation of castor oil with
ethylene oxide. Castor oil is generally composed of about 87% ricinoleic
acid, 7% oleic acid, 3% linoleic acid, 2% palmitic acid, and 1% stearic
acid. The reaction of varying molar ratios of ethylene oxide with castor
oil yields different polyethoxylated castor oil derivatives. The
derivatives of the present invention include products resulting from the
reaction of from 2-200 moles of ethylene oxide per one mole of castor oil.
The derivatives can also be hydrogenated. The most preferred derivative is
known as Polyoxyl 35 Castor Oil, also known as Cremophor EL (available
from BASF Corp., Parsippany, N.J.).
The compositions can also include ophthalmologically acceptable
preservatives, viscosity enhancers, penetration enhancers, buffers, sodium
chloride, mannitol, and water to form aqueous, sterile ophthalmic
suspensions or solutions. Furthermore, the compositions may contain a
thickener such as cellulosics (e.g. hydroxymethylcellulose,
hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose),
polyvinylpyrrolidone, carbomers or the like to improve the retention of
the medicament in the conjunctival sac.
The CAI compositions of the present invention are preferably formulated as
topical ophthalmic suspensions or solutions, with a pH of about 4.0-8.0,
preferably 4.0-6.0 for solutions and 6.0-8.0 for suspensions. The CAIs
will normally be contained in these formulations at concentrations of
0.1-10 weight/volume percent (wt/v %), but preferably about 0.25-5.0 wt/v
%. The polyethoxylated ether derivative of castor oil is present at
concentrations between 0.01-10.0 wt/v %, preferably 0.5-3.0 wt/v %. The
formulations will also preferably contain a preservative, such as,
benzalkonium chloride, at concentrations from 0.001-0.1 wt/v %.
Thus, for topical treatment of glaucoma and ocular hypertension, one to
three drops of these formulations would be delivered to the surface of the
eye one to four times a day according to the routine discretion of a
skilled clinician.
The preferred composition is set forth in Example 3. All compositions can
be formulated according to the routine discretion of one skilled in the
ophthalmic formulations art.
EXAMPLE 1
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3,4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide (1-methyl)ethyl ester
hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.08%
Cremophor EL 1.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 2
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3, 4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide ethyl ester hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.08%
Cremophor EL 1.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 3
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3, 4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide ethyl ester hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.08%
Cremophor EL 1%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 4
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3, 4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide ethyl ester hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.08%
Cremophor EL 0.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 5
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3, 4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide ethyl ester hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.08%
Cremophor EL 0.25%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 6
(R)-(+)-6-(Aminosulfonyl)-4-ethylamino-3, 4-dihydro-2H-thieno[3,2-e]-1,
2-thiazine-2-butanoic acid 1, 1-dioxide ethyl ester hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 0.324%
Cremophor EL 1.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 7
(S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.12%
Cremophor EL 1.5%
Dibasic Sodium Phosphate
0.1%
(Anhydrous), USP
Monobasic Sodium Phosphate
0.02%
(Monohydrate), USP
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 8
(S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 2.24%
Cremophor EL 1.5%
Dibasic Sodium Phosphate
0.1%
(Anhydrous), USP
Monobasic Sodium Phosphate
0.02%
(Monohydrate), USP
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 9
(S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 2.24%
Cremophor EL 1.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 10
(S,S)-(-)-4-Ethylamino-5,
6-dihydro-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide 7, 7-dioxide
hydrochloride (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 1.12%
Cremophor EL 1.5%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
EXAMPLE 11
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 0.5%
Cremophor EL 1.0%
Dibasic Sodium Phosphate
0.2%
(Anhydrous), USP
Mannitol 4.0%
Disodium EDTA (Edetate Disodium)
0.1%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 7.4
Purified Water qs 100%
______________________________________
EXAMPLE 12
4-Ethylamino-3,4-dihydro-2-(3-methoxy)propyl-2H-thieno[3,2-e]-1,
2-thiazine-6-sulfonamide 1, 1-dioxide (CAI)
______________________________________
Concentration
Ingredient (wt./v %)
______________________________________
CAI 0.4%
Cremophor EL 3.0%
Sodium Acetate (Trihydrate)
0.1%
Mannitol 4.1%
Disodium EDTA (Edetate Disodium)
0.01%
Benzalkonium Chloride Solution
0.01%
Hydroxypropyl Methylcellulose (2910)
0.8%
(E4M)
Hydrochloric Acid/Sodium Hydroxide
pH 5.0
Purified Water qs 100%
______________________________________
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